PMID- 29728112 OWN - NLM STAT- MEDLINE DCOM- 20190708 LR - 20231213 IS - 1479-5876 (Electronic) IS - 1479-5876 (Linking) VI - 16 IP - 1 DP - 2018 May 4 TI - Connexin32 plays a crucial role in ROS-mediated endoplasmic reticulum stress apoptosis signaling pathway in ischemia reperfusion-induced acute kidney injury. PG - 117 LID - 10.1186/s12967-018-1493-8 [doi] LID - 117 AB - BACKGROUND: Ischemia-reperfusion (I/R)-induced acute kidney injury (AKI) not only prolongs the length of hospital stay, but also seriously affects the patient's survival rate. Although our previous investigation has verified that reactive oxygen species (ROS) transferred through gap junction composed of connexin32 (Cx32) contributed to AKI, its underlying mechanisms were not fully understood and viable preventive or therapeutic regimens were still lacking. Among various mechanisms involved in organs I/R-induced injuries, endoplasmic reticulum stress (ERS)-related apoptosis is currently considered to be an important participant. Thus, in present study, we focused on the underlying mechanisms of I/R-induced AKI, and postulated that Cx32 mediated ROS/ERS/apoptosis signal pathway activation played an important part in I/R-induced AKI. METHODS: We established renal I/R models with Cx32(+/+) and Cx32(-/-) mice, which underwent double kidneys clamping and recanalization. ROS scavenger (N-acetylcysteine, NAC) and ERS inhibitors (4-phenyl butyric acid, 4-PBA, and tauroursodeoxycholic acid, TUDCA) were used to decrease the content of ROS and attenuate ERS activation, respectively. RESULTS: Renal damage was progressively exacerbated in a time-dependent manner at the reperfusion stage, that was consistent with the alternation of ERS activation, including glucose regulated protein 78 (BiP/GRP78), X box-binding protein1, and C/EBP homologous protein expression. TUDCA or 4-PBA application attenuated I/R-induced ERS activation and protected against renal tubular epithelial cells apoptosis and renal damage. Cx32 deficiency decreased ROS generation and distribution between the neighboring cells, which attenuated I/R-induced ERS activation, and improved cell apoptosis and renal damage. CONCLUSION: Cx32 mediated ROS/ERS/apoptosis signal pathway activation played an important part in I/R-induced AKI. Cx32 deficiency, ROS elimination, and ERS inhibition all could protect against I/R-induced AKI. FAU - Gu, Yu AU - Gu Y AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, China. FAU - Huang, Fei AU - Huang F AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, China. FAU - Wang, Yanling AU - Wang Y AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, China. FAU - Chen, Chaojin AU - Chen C AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, China. FAU - Wu, Shan AU - Wu S AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, China. FAU - Zhou, Shaoli AU - Zhou S AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, China. 13610272308@139.com. FAU - Hei, Ziqing AU - Hei Z AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, China. heiziqing@sina.com. FAU - Yuan, Dongdong AU - Yuan D AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, China. yuandongdong123@126.com. LA - eng GR - 2013B051000035/Science and Technology Project of Guangdong Province/International GR - 81571926/National Natural Science Foundation of China/International GR - 81401628/National Natural Science Foundation of China/International GR - 81372090/National Natural Science Foundation of China/International GR - 81772127/National Natural Science Foundation of China/International GR - 81500493/National Natural Science Foundation of China/International GR - 201508030003/Guangzhou Science and Technology Plan/International GR - 201607010233/Guangzhou Science and Technology Plan/International GR - 17ykpy55/Outstanding Young Teacher Training Program of Sun Yat-sen University/International GR - 2015A030313098/Natural Science Foundation of Guangdong Province/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180504 PL - England TA - J Transl Med JT - Journal of translational medicine JID - 101190741 RN - 0 (Connexins) RN - 0 (Endoplasmic Reticulum Chaperone BiP) RN - 0 (Hspa5 protein, mouse) RN - 0 (Phenylbutyrates) RN - 0 (Reactive Oxygen Species) RN - 516-35-8 (Taurochenodeoxycholic Acid) RN - 60EUX8MN5X (ursodoxicoltaurine) RN - 7WY7YBI87E (4-phenylbutyric acid) RN - WYQ7N0BPYC (Acetylcysteine) SB - IM EIN - J Transl Med. 2020 May 27;18(1):212. PMID: 32460807 MH - Acetylcysteine/pharmacology MH - Acute Kidney Injury/*etiology/*metabolism MH - Animals MH - *Apoptosis/drug effects MH - Connexins/*metabolism MH - Endoplasmic Reticulum Chaperone BiP MH - *Endoplasmic Reticulum Stress/drug effects MH - Epithelial Cells/drug effects/pathology MH - Gene Deletion MH - Gene Knockout Techniques MH - Kidney/pathology MH - Male MH - Mice, Inbred C57BL MH - Phenylbutyrates/pharmacology MH - Reactive Oxygen Species/*metabolism MH - Reperfusion Injury/*complications MH - *Signal Transduction/drug effects MH - Taurochenodeoxycholic Acid/pharmacology MH - Gap Junction beta-1 Protein PMC - PMC5935959 OTO - NOTNLM OT - Acute kidney injury OT - Connexin32 OT - Endoplasmic reticulum stress OT - Reactive oxygen species EDAT- 2018/05/08 06:00 MHDA- 2019/07/10 06:00 PMCR- 2018/05/04 CRDT- 2018/05/06 06:00 PHST- 2017/11/11 00:00 [received] PHST- 2018/04/21 00:00 [accepted] PHST- 2018/05/06 06:00 [entrez] PHST- 2018/05/08 06:00 [pubmed] PHST- 2019/07/10 06:00 [medline] PHST- 2018/05/04 00:00 [pmc-release] AID - 10.1186/s12967-018-1493-8 [pii] AID - 1493 [pii] AID - 10.1186/s12967-018-1493-8 [doi] PST - epublish SO - J Transl Med. 2018 May 4;16(1):117. doi: 10.1186/s12967-018-1493-8.